1. Field of the Invention
This invention relates to a reproducible process for the preparation of 6-(5-chloro-2-pyridinyl)-6,7-dihydro-7-oxo-5H-pyrrolo-[3,4-b]pyrazin-5-yl-4-methyl piperazine-1-carboxylate also known as zopiclone and it's intermediate 6-(5-chloropyridyl-2-yl)-5-hydroxy-7-oxo-5,6 dihydropyrrolo[3,4-b]pyrazine. The said invention further relates to an effective method for resolution of zopiclone into its enantiomers and furthermore provides a method of recycling of (R)-zopiclone.
2. Description of the Related Art
6-(5-chloro-2-pyridinyl)-6,7-dihydro-7-oxo-5H-pyrrolo-[3,4-b]pyrazin-5-yl-4-methyl piperazine-1-carboxylate, known as zopiclone under its international non-proprietary name, is a hypnotic agent of cyclopyrrolone class possessing a pharmaceutical profile similar to that of benzodiazepines and having high efficacy and low toxicity. The S-enantiomer or (+) zopiclone is less toxic, more active than its other enantiomer and is currently sold under the brand name of Lunesta for the treatment of insomnia. Zopiclone can be represented by Formula-I and was disclosed in U.S. Pat. No. 3,862,149 in its racemic form.

The process for preparing Zopiclone and its intermediate were first disclosed in U.S. Pat. No. 3,862,149 and U.S. Pat. No. 4,220,646. A method of treating sleep disorders in a human using (+) Zopiclone substantially free from (−) zopiclone are described in U.S. Pat. No. 5,786,357 and WO/93/10788 respectively.
U.S. Pat. No. 3,862,149 describes a process for preparing zopiclone. The process comprises reacting 2-amino-5-chloropyridine with pyrazine 2,3-dicarboxylic acid anhydride to obtain 3-(5-chloropyrid-2-yl)carbamoyl-pyrazine-2-carboxylic acid, which is further treated with thionyl chloride to obtain 6-(5-chloropyrid-2-yl)-5,7-dioxo-5,6-dihydro-5H-pyrrolo[3,4-b]pyrazine 6-(5-chloropyrid-2-yl)-5,7-dioxo-5,6-dihydro-5H-pyrrolo[3,4-b]pyrazine is reduced using potassium borohydride in a mixture of dioxane and water followed by neutralization with acetic acid to obtain 6-(5-chloropyrid-2-yl)-5-hydroxy-7-oxo-5,6-dihydro-5H-pyrrolo[3,4-b]-pyra-zine. The reaction of 6-(5-chloropyrid-2-yl)-5-hydroxy-7-oxo-5,6-dihydro-5H-pyrrolo[3,4-b]pyra-zine with 1-chlorocarbonyl-4-methyl piperazine in anhydrous dimethyl formamide and sodium hydride (50% dispersion in mineral oil) yields the final product, Zopiclone.
The above reaction involves multistage synthesis and many intermediates resulting in poor yields of the final product zopiclone. Further, thionyl chloride is toxic, corrosive, a potential lachrymator and also difficult to handle when used on an Industrial scale.
CZ 288047 discloses a process for making a zopiclone intermediate 6-(5-chloropyrid-2-yl)-5-hydroxy-7-oxo-5,6-dihydropyrrolo[3,4-b]-pyrazine, which comprises a selective reduction of 6-(5-chloropyrid-2-yl)-5,7-dioxo-5,6-dihydropyrrolo[3,4-b]-pyrazine by using potassium borohydride in liquid organic amide in the presence of water at a temperature of 70° C. However, this process discloses neither selectivity nor yield and purity of product.
In Indian Published Patent Application No. 645/MUM/2004 discloses the reaction of pyrazine-2,3-dicarboxylic acid with acetic anhydride and concomitant reaction with 2-amino-5-chloro pyridine at a temperature of 120-130° C. in a mole ratio 1.23:1 to obtain 6-(5-chloropyrid-2-yl)-5,7-dioxo-5,6-dihydropyrrolo[3,4-b]pyrazine, which is selectively reduced with sodium borohydride in the presence of organic solvent-water system. The product, 6-(5-chloropyrid-2-yl)-5-hydroxy-7-oxo-5,6-dihydropyrrolo[3,4-b]pyrazine (V) is reacted with 1-chlorocarbonyl-4-methyl piperazine in pyridine and methylene chloride system to yield 6-(5-chloro-2-pyridinyl)-6,7-dihydro-7-oxo-5H-pyrrolo-[3,4-b]pyrazin-5-yl-4-methyl piperazine-1-carboxylate (zopiclone).
US2007/0054914A1 describes the reaction of 6-(5-chloropyridyl-2-yl)-5-hydroxy-7-oxo-5,6-dihydropyrrolo[3,4-b]pyrazine and 1-chlorocarbonyl-4-methylpiperazine hydrochloride using an inorganic base and phase transfer catalyst in a mixture of organic solvents and water at −80 to 50° C. The obtained zopiclone is recrystallized from suitable solvent/solvent mixtures followed by resolution of racemic zopiclone using an enantiomerically pure di-toluoyl tartaric acid or its hydrates to obtain eszopiclone.
In some of these process steps, the reactants, per se, are the same but employ varying conditions to achieve better purity or yield. Although some of the problems are solved by modifying the reaction conditions or route of synthesis as taught by the prior art, there still exists problems like polymerization of intermediates due to the lengthy reaction periods and high temperatures, which need to be investigated.
The sodium hydride isopotential hazardous due to problems associated with handling on a large scale. The reactant, 1-chlorocarbonyl-4-methylpiperazine as a base on a commercial scale is unstable (Ref. US patent 2007/0054914 A1) as well as commercial unavailable. The use of pyridine on a large scale poses environmental hazards.
The process for resolving zopiclone is described in EP609210, wherein racemic zopiclone is dissolved along with D(+)-O,O′-dibenzoyl tartaric acid in methylene chloride to obtain diastereomeric dibenzoyl tartrate salt, followed by recrystallization in 44 volumes of acetonitrile, then followed by two recrystallizations from 17 volumes of methylene chloride-acetonitrile mixture (47:53) to obtain pure diastereomeric salt with an overall yield of 36%. The eszopiclone (crude) is isolated from dibenzoyl tartaric acid salt followed by recrystallization from acetonitrile yields pure eszopiclone with an overall yield of 23%. The main disadvantage of this process is the use of large volumes of solvent mixtures, which is difficult to recover.
There remains a need to provide an alternative to the prior art processes, which is cost-effective, feasible and highly reproducible on an industrial scale with high yield and purity, which has become the subject matter of the present invention.